Preliminary Efficacy, Safety and Pharmacokinetics Study of Nepadutant in Infant With Feeding Intolerance: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Preliminary Efficacy, Safety and Pharmacokinetics Study of Nepadutant in Infant With Feeding Intolerance (NCT01532518), a randomized phase 2 study. The primary outcome is The Absolute Differences of I-GERQ-R Total Score at V3 (End of First Week of Treatment) Respect to the Baseline (V2)..

2. Clinical Question

3. Trial Design

This was a phase 2, completed trial with 27 enrolled participants. The registry describes it as randomized, open label, and parallel. It also describes a multicenter, ascending-dose study in which participants received nepadutant. The method of randomization, the allocation process, and whether allocation was concealed are not reported in the registry record. Masking was listed as none.

The three cohort descriptions specify different dose sequences. Cohort 1 received nepadutant low dose (0.1mg/kg) for 7 days followed by medium dose (0.5mg/kg) for an additional 7 days. Cohort 2 received medium dose (0.5mg/kg) for 7 days followed by high dose (1mg/kg) for an additional 7 days. Cohort 3 received low dose (0.1mg/kg) for 7 days followed by high dose (1mg/kg) for an additional 7 days. These are sequential exposures, not descriptions of a concurrent placebo group.

The primary outcome was the difference in I-GERQ-R total score at V3, the end of the first treatment week, relative to baseline at V2. The outcome population is described as infants who received at least one dose. That endpoint timing means the primary result concerns the first treatment week, rather than the full sequence of two 7-day periods.

The stated purpose was to obtain preliminary information on symptom relief across three ascending oral dose levels and to assess drug exposure for future dose and schedule selection. The protocol’s detailed rationale for the enrollment target, a prespecified statistical analysis plan, and the basis for the cohort sizes are not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Infants with feeding intolerance who received at least 1 dose of nepadutant. In the 3rd cohort 1 subject didn't report I-GERQ-R score at randomization. In the 1rst cohort 1 patient early terminated after V2.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

Population: Infants with Feeding Intolerance

6. Primary Endpoint

The registry lists the primary outcome as The Absolute Differences of I-GERQ-R Total Score at V3 (End of First Week of Treatment) Respect to the Baseline (V2)., measured over Baseline (V2) and end of first week of treatment (V3).

The primary endpoint is the mean difference in I-GERQ-R total score between baseline at V2 and the end of the first treatment week at V3. The Infant Gastroesophageal Reflux Questionnaire Revised has a total score from 0 to 42, with higher values reflecting worse outcome. Its 12 questions cover regurgitation, crying, feeding refusal, apnea or cyanosis, hiccups, and arching. Items have response scores that vary according to the number of possible options, and item scores are summed to form the total score.

This questionnaire gives a structured way to quantify several symptoms associated with feeding intolerance in infants. A change in total score can describe whether reported symptom burden shifted over the measured interval. The registry notes that scores at V2 serve as baseline values for evaluating V3. It also notes that a score greater than 15 is the minimum for diagnosis, but that threshold is not itself the primary endpoint: the reported endpoint is the change in the total score.

The endpoint is measured after the first week, so it does not directly summarize the effects of the second treatment week. It is a continuous measure, and the registry reports a mean and standard deviation for each cohort. Those summaries describe the observed score changes; without a posted comparison and uncertainty interval, they do not by themselves establish how precise a cohort’s mean is or whether observed differences between cohorts exceed chance variation.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a continuous score, and the registry reports the mean change and standard deviation within each cohort. These statistics answer different questions. The mean describes the average observed change in a cohort. The standard deviation describes the variability of participant-level values around that average. A mean does not imply that every participant changed by that amount, and the standard deviation is not a confidence interval for the mean.

What does a mean change describe?

The endpoint compares I-GERQ-R total score at V3 with the baseline score at V2. A negative posted mean indicates that the average follow-up score was lower than the baseline score under the endpoint’s stated comparison. Since higher I-GERQ-R values represent worse outcome, a lower score corresponds to a less severe questionnaire score. This description concerns the measured score only; it does not identify why the score changed.

The three cohort means are -6.8, -7.6, and -6.8. They are summaries of the observed participants in each cohort, not direct contrasts between dose levels. To estimate a between-group effect, an analysis would ordinarily compare outcomes across groups with a defined contrast and report an estimate with its uncertainty. The registry record does not report that kind of primary-outcome analysis.

Why does variability matter?

The standard deviations are 9.55, 5.5, and 5.81 in Cohorts 3, 2, and 1, respectively. When participant values vary widely, a cohort mean may give an incomplete picture of individual outcomes. The standard deviation provides context for that variability, but it does not show the range of scores, the shape of their distribution, or how certain the mean estimate is. Those details are not reported in the registry record.

A confidence interval is a statistical range that expresses uncertainty about an estimated quantity under the method used to construct it. In general, a narrower interval indicates greater precision, while a wider interval indicates less precision. No confidence interval for the primary endpoint is posted. Without one, the precision of each cohort mean cannot be directly assessed from the registry results. A p-value, if reported, would address compatibility with a specified statistical null model; it would not measure the size or clinical importance of an effect. No primary-outcome p-value is reported.

Why is a comparator important?

A within-cohort change compares participants with their own baseline, but it does not provide the same information as a randomized contrast between a treatment group and a concurrent control group. Over time, symptoms can change for reasons other than the intervention. A concurrent comparator can help estimate the difference in changes between groups, subject to the study design and analysis. The listed treatment cohorts all receive nepadutant in different sequences, and no untreated or placebo cohort is described. Although the registry identifies the study as randomized and parallel, the randomization method and a prespecified comparison among cohorts are not reported in the registry record.

Open-label conduct is also relevant when interpreting a symptom questionnaire. In general, knowledge of assigned treatment can influence reporting or assessment. Randomization can help balance some group differences, but it does not mask treatment, and it does not create a comparator that is absent from the described arms. The posted data should therefore be treated as descriptive and preliminary.

What do the planning illustrations mean?

Any sample-size planning illustration based on an observed effect is a hypothetical calculation for a future study, not an account of the design that generated these results. The stated illustration assumptions use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the target effect is a stated fraction of the observed effect. Such calculations depend on assumptions about the effect to detect and the comparison being planned. They do not show that the current trial had a particular probability of detecting an effect, and they are not observed power. The registry’s own sample-size justification is not reported in the registry record.

The illustration describes participants per arm for 80% power or other stated planning targets when applicable. These are prospective planning quantities, not observed participant counts or results. The registry record does not report an analysis for the two-arm comparison needed to anchor a comparative power interpretation. The illustration should consequently be understood as a planning aid, not evidence for a treatment effect.

Why can over-dispersion matter?

In general, over-dispersion means that observed variation is greater than a statistical model assumes. When a model understates variability, its uncertainty estimates can be too small and its inferential results overly confident. The primary endpoint is summarized using means and standard deviations, and no model-based comparison is posted. The registry does not report an over-dispersion assessment or a model for this endpoint, so no such adjustment can be inferred.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Cohort 3", "Cohort 2", "Cohort 1")
n   <- c(5, 15, 5)
m   <- c(-6.8, -7.6, -6.8)
sp  <- c(9.55, 5.5, 5.81)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Cohort 3  5  -6.800  9.550  -18.658  5.058
CARM  Cohort 2  15  -7.600  5.500  -10.646  -4.554
CARM  Cohort 1  5  -6.800  5.810  -14.014  0.414

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 10 outcome measures and five posted secondary outcomes. The secondary outcomes include adverse events by treatment dose level and population pharmacokinetic analyses of the plasma concentration-time course. The pharmacokinetic analysis description appears repeatedly in the outcome listing. The registry does not report a multiplicity strategy, such as a hierarchy of confirmatory outcomes or an adjustment for testing several outcomes. When multiple outcomes are examined, the chance of at least one apparently notable result can increase; in general, a prespecified strategy helps readers understand how multiple findings were handled. No multiplicity-adjusted result is reported.

The registry lists no analyses for the primary endpoint. In particular, it does not post a formal statistical comparison among cohorts, confidence intervals, or p-values for the mean changes. The record does not report whether interim analyses were planned or conducted, or whether any outcome analyses were prespecified beyond the endpoint description. These details are not reported in the registry record.

The primary outcome population is described as infants who received at least one dose of nepadutant. The record notes that one Cohort 3 participant did not report an I-GERQ-R score at randomization and that one Cohort 1 participant terminated early after V2. It does not state whether the missing baseline score was excluded, imputed, or handled in another way, nor does it explain how the early termination affected the endpoint analysis. The extent of any additional missing data and the analysis population used for each cohort are not reported in the registry record.

In general, different missing-data approaches can lead to different estimates, especially when missingness is related to participant outcomes. Without a stated approach and participant flow for this endpoint, the posted cohort summaries cannot be assumed to represent a particular intention-to-treat or per-protocol analysis.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: laryngeal edema-post intubation (8.3%), hospitalisation for investigation for suspected seizures (4.8%).

The registry’s adverse-event summaries are organized by dose level. At the high dose level (1.0 mg/Kg), 1 of 21 participants at risk was affected by a serious adverse event, and 12 of 21 were affected by other adverse events. At the medium dose level (0.5mg/Kg), 0 of 21 were affected by a serious adverse event, and 2 of 21 were affected by other adverse events. At the low dose level (0.1mg/Kg), 1 of 12 was affected by a serious adverse event, and 8 of 12 were affected by other adverse events.

These are dose-level summaries, not necessarily mutually exclusive groups of participants: the cohort descriptions include successive dose exposures. They should not be added across dose levels to produce a unique-participant total. The record lists laryngeal edema-post intubation at 8.3% and hospitalisation for investigation for suspected seizures at 4.8% among the top serious-event terms. It does not assign those listed terms to a specific dose group in the posted summary.

The registry does not report deaths in these summaries. A missing death value should not be interpreted as zero. These descriptive safety counts do not establish comparative risk, particularly without a control group or a reported analysis accounting for repeated dose exposure. They also do not determine the cause of any event.

13. What the Result Does, and Does Not, Mean

The posted primary outcome means describe changes in an infant symptom questionnaire during the first treatment week. The average score was lower at the end of that week than at baseline in each listed cohort, as indicated by negative mean changes. The standard deviations show that individual changes varied around those means. Together, these summaries offer preliminary descriptive information about the score in participants who received nepadutant.

They do not establish that nepadutant caused the observed changes. The study is open label and does not list a placebo or untreated comparator. Symptoms may change over time for reasons unrelated to treatment, and questionnaire responses may be affected by awareness of treatment. The record also does not report a statistical test or interval estimate for the primary outcome, so the precision of the cohort means and the strength of evidence for differences cannot be quantified from the posted results.

The cohort means should not be interpreted as proof that one dose sequence is better than another. Cohorts followed different sequences, with exposure changing over time, and the registry does not report a defined statistical contrast between them. The sequence descriptions also mean that the dose-level adverse-event summaries should not be treated as separate, independent treatment arms.

The listed adverse-event figures describe affected participants at risk within each dose-level summary. The serious-event terms and percentages provide additional descriptive information, but the record does not tie those terms to particular dose groups or report a comparative safety analysis. The absence of a reported death count is not evidence that no deaths occurred.

Overall, these findings are preliminary and useful for understanding what the registry records about symptoms, exposure sequences, and adverse events. They do not establish a causal treatment effect, comparative dose efficacy, or definitive safety profile. The registry’s stated aim of informing future dose and schedule selection is consistent with an exploratory study; a controlled, fully reported analysis would be needed to answer comparative questions more directly.

14. Why This Trial Matters Statistically

This trial is statistically notable because it combines randomized and parallel design labels with cohort descriptions in which all participants receive nepadutant through different dose sequences. Those features make it important to distinguish the study’s design labels from the comparisons actually described in the posted outcome results. Without a listed placebo or untreated group and without a reported between-cohort analysis, the primary outcome summaries are within-cohort descriptions rather than comparative effect estimates.

The outcome is also a patient- or caregiver-reported symptom score measured before treatment and at the end of the first treatment week. Its total score combines several symptom domains, which creates a compact continuous measure but can conceal differences across individual symptoms. The registry gives a scale range and direction, allowing the mean changes to be interpreted, yet does not report item-level results or uncertainty intervals for the cohort means.

The small cohort outcome counts of 5, 15, and 5 make the reported variability especially relevant when reading the means. The standard deviations indicate that participant scores varied, while the missing confidence intervals leave the precision of those means unquantified. These considerations illustrate why descriptive effect estimates, measures of spread, sample size, and analysis details should be read together.

The study’s stated purpose includes preliminary dose-effect and pharmacokinetic information. The registry lists pharmacokinetic secondary outcomes, but the posted primary endpoint does not establish a dose-response relationship. Separating exploratory signals from confirmatory comparisons is essential when interpreting a small, open-label study and planning subsequent research.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The main limitation for interpretation is the absence of a concurrent control group in the listed cohorts. All three cohorts receive nepadutant, and their treatments differ by sequence. The negative score changes therefore describe change over time among treated participants; they do not isolate the effect of the drug from natural symptom change or other influences.

The study is open label, and the primary measure is a questionnaire-based total score. Awareness of treatment may influence symptom reporting or assessment. The registry does not report whether any procedures were used to reduce this risk. The total score also combines multiple symptom domains, and the posted primary result does not show whether changes were similar across those domains.

The primary outcome data are limited by small cohort counts and substantial reported variation. The registry notes one missing score at randomization in Cohort 3 and an early termination after V2 in Cohort 1. The method for handling these cases is not reported in the registry record. Confidence intervals, primary-outcome p-values, adjusted analyses, and details of the statistical analysis plan are also not reported.

The randomization process is not described, and the relationship between randomization and the listed ascending-dose cohorts is unclear from the registry entry. There is no reported comparative analysis establishing whether the cohort means differ. As a result, the observed mean ordering cannot support a dose comparison on its own.

Safety summaries are presented by dose level even though the cohort descriptions include successive exposure periods. The summaries may therefore reflect repeated exposure of participants across dose levels. The registry does not provide an analysis accounting for this structure, a control-group safety comparison, or a group assignment for the named serious-event terms. These limitations restrict conclusions about comparative safety as well as efficacy.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Preliminary Efficacy, Safety and Pharmacokinetics Study of Nepadutant in Infant With Feeding Intolerance — NCT01532518.
• Registry record last updated 2023-05-06; status last verified 2022-08.
• Results first posted 2023-05-06.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

NCT01532518 is a completed phase 2 randomized, open-label, parallel study of nepadutant in infants with feeding intolerance. It enrolled 27 participants and described three ascending dose sequences, each lasting two successive 7-day periods. No placebo or untreated cohort is listed.

The primary endpoint was the mean I-GERQ-R total-score difference between baseline at V2 and the end of the first treatment week at V3. The cohort means were -6.8, -7.6, and -6.8, with standard deviations of 9.55, 5.5, and 5.81, respectively. The registry does not report a formal primary-outcome comparison or confidence intervals.

Adverse events were summarized by dose level. The registry also lists pharmacokinetic secondary outcomes. The method of randomization, missing-data handling, multiplicity strategy, and detailed statistical analysis plan are not reported in the registry record. The results are descriptive and preliminary, with no concurrent control comparison reported.